Rosenthal, 3·* David T. Harris, 4 John i"lorton,5 and John H. Glic::k6
`
`SUMMARY
`
`During phase I trials with maytansine some activity against lymphoma
`and lymphocytic leul{emia was noted. Therefore, a phase II trial of
`maytansine in patients with advanced lymphomas refractory to
`conventional chemotherapy was begun. There were three partial responders
`(10%) among 31 patients entered in the trial. Toxicity was acceptable;
`gastrointestinal and neurologic side effects were the most common. Little
`myelotoxicity and no hepatotoxicity were observed. We conclude that
`maytansine has very limited activity in heavily pretreated patients with
`Hodgkin's disease and non-Hodgldn's lymphomas.
`
`[Cancer Treat Rep 64:1115-1117, 1980]
`
`Maytansine is a naturally occurring ansa macro(cid:173)
`lide originally isolated from the stem bark of the
`East African shrub Maytenus ovatus (1). Its mech(cid:173)
`anism of action is similm· to that of the vinca alka(cid:173)
`loids. Maytansine produces metaphase arrest by in(cid:173)
`terference with mitotic spindle formation caused by
`inhibition of tubulin polymerization. Unlike vincris(cid:173)
`tine, however, maytansine binds to tubulin irre(cid:173)
`versibly and produces an irreversible stathmoki(cid:173)
`netic effect (2,3).
`Early clinical trials with maytansine demon(cid:173)
`strated acceptable toxic effects including nausea,
`vomiting, diarrhea, and abnormalities in hepatic
`function tests (4,5). Little myelosuppression other
`than sporadic thrombocytopenia, especially in pa-
`
`1Received Dec 14, 1979; revised Feb 28, 1980; accepted Mar
`11, 1980.
`2This study was conducted by the Eastern Cooperative On(cid:173)
`cology Group (Paul P. Ca·rbone, chairman, CA-21115) and sup(cid:173)
`ported by Public Health Service grants CA-11083 (S. Rosentlwl),
`CA-18281 (D. T. Han·is), CA-06594 (J. Ho1·ton), and CA-15488
`(J. H. Glick) from the National Cancer Institute, National In(cid:173)
`stitutes of Health, Department of Health and Human Services.
`S. Rosenthal was supported in part by an American Cancer
`Society Junior Faculty Clinical Fellowship.
`3University of Rochester Cancer Center, NY.
`4American Oncologic Hospital, ·Philadelphia, PA.
`5Albany Medical College, NY.
`6Hospital of the University of Pennsylvania, Philadelphia.
`*Rep·rint t•equests to: Dr. Susan Rosenthal, Rochester General
`Hospital, 1425 Portland Ave, Rochester, NY 14621.
`
`tients with pre-existing liver disease, was encoun(cid:173)
`tered (6). Extravasation of the drug caused phlebitis
`and local necrosis (5). Dose-related neurotoxicity
`included both central (lethargy, dysphoria, and drop
`in performance status) and peripheral (paresthe(cid:173)
`sias, jaw pain, muscle weakness, and loss of deep
`'tendon reflexes) effects. Patients with pre-existing
`vincristine or carcinomatous neuropathies had
`greater neurologic toxic effects from maytansine
`(5).
`To date, phase II trials ofmaytansine have shown
`little activity against breast cancer (7), melanoma
`(7), lung cancer (8), and colorectal cancer (9). In
`September 1977, the Eastern Cooperative Oncology
`Group initiated a phase II trial of maytansine in
`patients with advanced lymphomas. refractory to
`conventional chemotherapy.
`
`METHODS
`
`All patients had advanced (stage III or IV) his(cid:173)
`tologically documented Hodgkin's disease m· non(cid:173)
`Hodgkin's lymphoma and were no longer responsive
`to conventional chemotherapy. Twenty-nine pa(cid:173)
`tients had received prior treatment with vinca al(cid:173)
`kaloids, and one had received VM-26 as well. Many
`patients had received prior radiation therapy (table
`1). Each patient had at least one site of measurable
`disease. Criteria for ineligibility included chemo-
`
`Cancer Treatment Reports Vol. 64, No. 1 Q-11, October/November 1 SBO
`
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`TABLE 1.-Pretreatment chm·acteristics of 31 patients with
`lymphoma treated with maytansine
`
`Characteristic
`
`No. of patients
`
`Histologic type
`Hodgkin's disease
`Non-Hodgkin's lymphoma
`
`Sex
`Males
`Females
`
`Median age in yrs (range): 56 (19-85)
`
`Performance status
`0--1
`2-3
`4
`
`Previous treatment
`Chemotherapy only
`Chemotherapy and radiotherapy
`
`Previous exposure to vinca alkaloids
`Vincristine
`Vinblastine
`Vincristine and vinblastine
`Neither
`
`Sites of measurable disease
`Lymph nodes
`Lung
`Liver
`Blood and marrow
`Skin
`Spleen
`
`9
`22
`
`21
`10
`
`11
`17
`3
`
`7
`24
`
`18
`1
`10
`2
`
`29
`7
`6
`5
`5
`1
`
`therapy within 2 weeks of entry in the study and
`an expected survival of < 2 months. None of the
`patients was clinically jaundiced, although several
`had abnormal liver function tests. Pretreatment
`characteristics of the 31 patients are summarized
`in table 1.
`Maytansine was administered by iv bolus injec(cid:173)
`tion over 3-5 minutes at a dose of 0.5 mg/m2 daily
`for 3 consecutive days, with each treatment cycle
`repeated at 3-week intervals. Patients with pre-ex(cid:173)
`isting liver disease and bilirubin or SGOT greater
`than twice normal received a 50% dose reduction.
`No dose adjustment was made for low peripheral
`blood cell counts resulting from prior therapy or
`disease involvement. Patients continued to receive
`therapy until disease progression. Those patients
`who had no change in measurable disease after
`three cycles of treatment were also considered to
`have failed maytansine treatment.
`Responses were defined by standard Eastern
`Cooperative Oncology Group criteria. A partial re(cid:173)
`sponse was defined as a > 50% reduction in the sum
`of the products of perpendicular diameters of meas(cid:173)
`urable lesions. Disease progression was defined as
`the unequivocal appearance of any new lesion or an
`increase of 25% in the product of the perpendicular
`diameters of any measurable lesion. Responses
`
`were recorded only if the observed improvement
`persisted for > 1 month. Duration of response was
`measured from the date treatment was started. All
`patients were considered evaluable for response,
`even if they received less than one full course of
`treatment.
`
`Therapeutic Effects
`
`Thirty-one patients were entered in the study.
`Six patients died within 4 weeks after starting ther(cid:173)
`apy. In each case death was thought to be due to
`progressive lymphoma and its complications rather
`than to maytansine treatment. Nineteen patients
`had progressive disease while receiving maytansine
`and three had no improvement. Three patients had
`partial responses; the response rate was 10%. De(cid:173)
`tails about the three responders are shown in table
`2.
`.
`For each of the responders, treatment was dis(cid:173)
`continued after three or four cycles even though
`responses were continuing. In two cases, the pa(cid:173)
`tients refused further maytansine because of toxic
`effects (paresthesias, diarrhea, nausea, and vom(cid:173)
`iting). In the patient with nodular mixed lymphoma,
`maytansine was withheld because of thrombocyto(cid:173)
`penia (30,000-70,000 cells/mm 3
`). Bone marrow in(cid:173)
`volvement was present, however, and it appears
`likely that the disease, rather than maytansine, was
`mainly i·esponsible for the thrombocytopenia. No
`improvement in platelet count was observed after
`maytansine was discontinued.
`The patient with nodular sclerosing Hodgkin's
`disease responded in his liver and peripheral nodes
`after one cycle of maytansine. He refused further
`treatment after the third cycle but remained in good
`partial remission with return to a normal activity
`schedule for a total of 13 months without additional
`therapy. At that point he relapsed in his peripheral
`nodes and liver and developed ascites.
`
`Toxic Effects
`
`Twenty-nine of the 31 patients were evaluable for
`toxic effects. The other two patients died within 4
`days after starting therapy. Hematologic toxicity
`was minimal. No patient had a wbc count of < 2500/
`mm", and only' two patients had wbc counts of
`< 4000/mm". No patient had a platelet count of
`< 30,000/mm", and only three patients had platelet
`counts of.< 100,000/mm". No thrombocytopenic
`hemorrhage or leukopenic infection occurred.
`Gastrointestinal side effects were the most com(cid:173)
`mon, usually occurring at the end of the treatment
`
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`

`TABLE 2.-Responders to maytansine
`
`Histologic type•·
`
`Stage
`
`P1·evious vinel'istine/
`vinblastinet
`
`Site of response
`
`Out·ation
`(mas)
`
`NM
`DPDL
`Hodgkin's disease (NS)
`
`IVB
`IVA
`IVA
`
`-I-
`+I-
`+I-
`
`Peripheral nodes
`Peripheral nodes
`Peripheral nodes, livec
`
`4
`4
`13
`
`*NM = nodular mixed lymphoma; DPDL = diffuse poorly differentiated lymphocytic lymphomD;
`NS = nodular sclerosis.
`tNo patients with previous VP-16-213 or VM-26 therapy.
`
`cycle or within a few days after treatment. Nine
`patients had gastrointestinal side effects (nausea,
`vomiting, and diarrhea), but in only one patient was
`the toxic effect considered severe. No patient with
`normal liver function tests at the start of treatment
`had evidence of hepatotoxicity while receiving may(cid:173)
`tansine. Eight patients with pre-existing liver func(cid:173)
`tion abnormalities had fluctuations in liver function
`tests while receiving maytansine, but in no patient
`could deterioration in liver function be clearly as(cid:173)
`cribed to maytansine treatment. There was no in(cid:173)
`dication of increased neurologic or hematologic tox(cid:173)
`icity in those patients with pre-existing liver disease
`who were treated with 50% doses of maytansine.
`
`DISCUSSION
`
`The response rate of the lymphoma patients
`treated with maytansine in this study was disap(cid:173)
`pointingly low. All of the patients had far-advanced
`disease and had undergone extensive previous
`chemotherapy with or without radiation therapy.
`In most patients maytansine was the third or fourth
`chemotherapy regimen employed. Most of the pa(cid:173)
`tients, however, were in reasonably good condition,
`and maytansine could be administered in an out(cid:173)
`patient setting in almost all instances. Neverthe(cid:173)
`less, the 10% response rate offers little encourage(cid:173)
`ment that maytansine, at least at this dose and
`schedule, will be of significant value in the treat-
`
`ment of Hodgkin's disease or non-Hodgkin's lym(cid:173)
`phoma. Further trials with this agent in patients
`with lymphoma are not warranted.
`
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`
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`3. JOHNSON RK, INOUYE T, and WoLPERT-DEFILIPPES MK.
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`maytansine in patient~ with advanced colorectal carcinoma.
`Cancer Treat Rep 62:1237-1238, 1978.
`
`Vol. 64, No. 1 o-11, October/November 1980
`
`1117
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`IMMUNOGEN 2004, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
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